Project Summary This project proposes an innovative multinuclear MRI approach to gain mechanistic insight into the exercise- associated adaptations in lower leg muscle function and peripheral nerve integrity of patients with diabetic peripheral neuropathy (DPN). A significant consequence of DPN is loss of peripheral nerve integrity, neurogenic muscle atrophy, fatty infiltration, and loss of muscle endurance. These synergistically contribute to altered gait, impaired balance, and increased fall risk, which can lead to bone fractures, poorly healing wounds, and chronic infections that often require an amputation. There are no therapies to prevent or reverse the progress of DPN. Preliminary single-group studies showed that a 10-week moderate-intensity supervised exercise program is well tolerated by patients with DPN, and improves nerve function, cutaneous innervation, and cardiovascular and macrovascular endothelial functions. However, the physiological basis of these effects is poorly defined. Our team is uniquely positioned to use novel multinuclear MRI technology to understand how exercise affects skeletal muscle and peripheral nerve integrity and function in patients with DPN. We will prescribe a 10-week exercise program, with both aerobic and strengthening components, to 50 DPN patients who will receive personal supervision from health professionals. Another 50 DPN patients will be randomly assigned to the non-exercising control group. We hypothesize that i) exercise will improve peripheral nerve integrity (fractional anisotropy will increase, and the apparent diffusion coefficient will decrease as measured using diffusion tensor imaging), ii) exercise will decrease plasma levels of oxidative stress, iii) exercise will improve DPN symptoms, assessed with the Michigan Neuropathy Screening Instrument. Our second aim is to determine the effect of exercise on lower leg muscle structure and function in DPN patients. We hypothesize that i) exercise will increase leg mitochondrial function, as defined by an increase in oxidative capacity (measured using phosphorus-MRI), ii) exercise will improve leg microvascular function, as defined by an increase in peak microvascular response (measured using BOLD-MRI), and iii) exercise will decrease intramuscular fat and increase levels of fat-free muscle (measured using IDEAL-MRI). Advanced multinuclear- MRI can provide mechanistic insight into exercise-related adaptations in patients with DPN. These include changes in intramuscular fat content, MV and metabolic functions of the skeletal muscle, as well as peripheral nerve function and integrity. Understanding these adaptations promises to reveal new ways to improve DPN symptoms after exercise interventions, better predict patient outcomes, and develop more effective treatments for DPN.